Human immunodeficiency virus type 1 (HIV-1) infection involves a selection bottleneck that leads to transmission of one or a few variants. C–C motif chemokine receptor 5 (CCR5) or C–X–C motif chemokine receptor 4 (CXCR4) can act as coreceptors for HIV-1 viral entry. However, initial infection mostly occurs via CCR5, despite abundant expression of CXCR4 on target cells. The host factors that influence HIV-1 susceptibility and selection during transmission are unclear. Here we conduct CRISPR–Cas9 screens and identify SLC35A2 (a transporter of UDP–galactose expressed in target cells in blood and mucosa) as a potent and specific CXCR4-tropic restriction factor in primary target CD4⁺ T cells. SLC35A2 inactivation, which resulted in truncated glycans, not only increased CXCR4-tropic infection levels but also decreased those of CCR5-tropic strains consistently. Single-cycle infections demonstrated that the effect is cell-intrinsic. These data support a role for a host protein that influences glycan structure in regulating HIV-1 infection. Host cell glycosylation may, therefore, affect HIV-1 selection during transmission in vivo.

人类免疫缺陷病毒 1 型 （HIV-1） 感染涉及导致一个或几个变体传播的选择瓶颈。C-C 基序趋化因子受体 5 （CCR5） 或 C-X-C 基序趋化因子受体 4 （CXCR4） 可以作为 HIV-1 病毒进入的辅助受体。然而，尽管 CXCR4 在靶细胞上大量表达，但初始感染主要通过 CCR5 发生。在传播过程中影响 HIV-1 易感性和选择的宿主因素尚不清楚。在这里，我们进行 CRISPR-Cas9 筛选并确定 SLC35A2（在血液和粘膜中的靶细胞中表达的 UDP-半乳糖转运蛋白）作为初级靶 CD4⁺ T 细胞中有效且特异性的 CXCR4-嗜性限制因子。SLC35A2失活导致聚糖截短，不仅增加了 CXCR4-tropic 感染水平，而且持续降低了 CCR5-tropic 菌株的感染水平。单周期感染表明这种影响是细胞内在的。这些数据支持影响聚糖结构的宿主蛋白在调节 HIV-1 感染中的作用。因此，宿主细胞糖基化可能会影响体内传播过程中 HIV-1 的选择。